Affinage

ATG4B

Cysteine protease ATG4B · UniProt Q9Y4P1

Length
393 aa
Mass
44.3 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATG4B is the cysteine protease that processes and deconjugates all four mammalian ATG8 homologues (LC3, GABARAP, GATE-16, Apg8L/ATG8L), positioning it as a central enzymatic node in the autophagy machinery (PMID:14530254, PMID:16704426). It is a papain-superfamily cysteine protease with a Cys74-His280-Asp278 catalytic triad whose active-site entrance is masked by a regulatory loop; substrate engagement is driven by LC3 Phe119 lifting this loop to admit the LC3 tail, while the N-terminal tail detaches to expose a flat surface compatible with access to membrane-bound LC3-PE (PMID:19322194, PMID:16325851). Recognition is bipartite and exquisitely sequence-specific: the LC3 ubiquitin-like core binds full-length ATG4B with low-nanomolar affinity and the ATG4B C-terminal tail contributes a ≥1000-fold affinity gain, while a 'molecular ruler' mechanism reading the LC3 C-terminal motif (Gln116/Phe119/Gly120) confers cleavage-site fidelity (PMID:32686895, PMID:36264309). ATG4B performs both pro-LC3 priming and LC3-PE delipidation, and its catalytic level must be balanced—dominant-negative ATG4B(C74A) sequesters LC3 and blocks autophagosome closure, whereas its delipidation activity controls LC3 membrane binding/dissociation dynamics and the efficiency of autophagosome formation at early autophagic membranes (PMID:19104152, PMID:34562084). ATG4B activity is governed by a dense layer of post-translational control: stimulatory phosphorylation at Ser383/Ser392 by MST4 and at Ser34 by PFKP enhances protease activity and flux, ULK1 phosphorylation at Ser316 inhibits it (reversed by PP2A-PP2R3B), and additional inhibitory inputs include UBE3C-mediated K33 ubiquitination at Lys119, EP300 acetylation at Lys39 (antagonized by SIRT2 deacetylation), S-nitrosation at Cys189/Cys292, and ROS/REDD1-TXNIP redox suppression; RNF5 ubiquitination controls the stability of the membrane-associated pool (PMID:29232556, PMID:33607258, PMID:28821708, PMID:38146933, PMID:36056541, PMID:25916556, PMID:23093945, PMID:28633005). At the transcriptional level, C/EBPβ, Egr-1, and HSF1 link ATG4B expression to adipogenesis and to radiation- and chemotherapy-induced protective autophagy (PMID:23754749, PMID:28134935, PMID:28889000). Beyond bulk autophagy, ATG4B delipidates LC3B from melanosomal membranes during melanosome trafficking, processes centrosomal LC3B to permit normal cell cycle progression, and promotes GABARAP-directed selective degradation of TBK1 to dampen type-I interferon signaling (PMID:28598240, PMID:37701987, PMID:37434364).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 High

    Establishing which enzyme processes the mammalian ATG8 family was prerequisite to understanding LC3 lipidation; activity-based profiling identified ATG4B as the single protease handling all four homologues.

    Evidence Activity-based protein profiling with electrophilic ubiquitin-like probes in cell lysates

    PMID:14530254

    Open questions at the time
    • Did not resolve substrate-specific kinetic differences among the four ATG8 homologues
    • No structural basis for recognition yet
  2. 2005 High

    Defining the catalytic machinery showed ATG4B is a papain-like cysteine protease, identifying the residues required for both precursor processing and deconjugation.

    Evidence X-ray crystallography at 2.0 Å plus active-site mutagenesis (Cys74, His280, Asp278; R229, W142)

    PMID:16325851

    Open questions at the time
    • Function of the auxiliary domain unresolved
    • No substrate-bound structure to explain selectivity
  3. 2006 Medium

    Genetic and reconstitution work confirmed ATG4B as the dominant LC3-processing enzyme and added Atg8L as a bona fide substrate, completing the substrate roster.

    Evidence In vitro cleavage and E1/E2 conjugation reconstitution; RNAi in PC12 cells; tissue expression profiling

    PMID:16704426 PMID:16874114

    Open questions at the time
    • Relative contributions of ATG4A/C versus ATG4B in vivo not delineated
    • Physiological meaning of high brain/testis expression untested
  4. 2009 High

    Substrate-bound structures and dominant-negative cell biology revealed how LC3 binding remodels the active site and why catalytic balance matters for autophagosome closure.

    Evidence Crystallography of inert ATG4B–LC3 complexes; overexpression of catalytically dead ATG4B(C74A) with autophagic-structure imaging

    PMID:19104152 PMID:19322194

    Open questions at the time
    • How the exposed flat surface engages membrane-bound LC3-PE not directly shown
    • Mechanism coupling delipidation to autophagosome sealing incomplete
  5. 2012 High

    Defining ATG4B turnover, RNF5 was shown to ubiquitinate the membrane-associated pool, establishing stability control as a regulatory layer over basal autophagy.

    Evidence Reciprocal co-IP, ubiquitination assays, RNF5−/− MEFs, domain-mapping mutants, bacterial infection model

    PMID:23093945

    Open questions at the time
    • Ubiquitin chain linkage and degradation route not fully defined
    • Selectivity for the membranal fraction mechanistically unexplained
  6. 2015 High

    A phospho-switch and redox sensing emerged as activity controls: Ser383/392 phosphorylation enhances delipidation activity while a REDD1/TXNIP-driven ROS pathway suppresses the redox-sensitive catalytic cysteine.

    Evidence In vitro hydrolase assays, atg4b−/− reconstitution, co-IP; ATG4B activity assays in REDD1/TXNIP knockout cells/mice

    PMID:25916556 PMID:26378241

    Open questions at the time
    • Identity of the kinase for Ser383/392 not established in these studies
    • Which cysteine(s) sense ROS not pinpointed here
  7. 2017 High

    Multiple opposing signaling inputs were resolved—MST4 (Ser383) and AKT (Ser34) stimulatory phosphorylation, ULK1 (Ser316) inhibitory phosphorylation reversed by PP2A, S-nitrosation, and Rab7b vesicular regulation—mapping ATG4B as a hub integrating stress and metabolic cues.

    Evidence In vitro kinase assays, phospho-mutants, phosphatase identification, S-nitrosation proteomics, co-IP/co-localization, xenograft and metabolic models

    PMID:28633005 PMID:28821708 PMID:28835545 PMID:29165041 PMID:29232556

    Open questions at the time
    • Hierarchy and crosstalk among these modifications unresolved
    • AKT-Ser34 effect on metabolism separated from autophagy raises unexplained mitochondrial role
    • Rab7b regulation mechanism (direct vs membrane recruitment) unclear
  8. 2017 Medium

    Transcriptional control of ATG4B was tied to physiology and disease via C/EBPβ (adipogenesis), Egr-1 (radioresistance), and HSF1 (chemoresistance) directly binding the promoter.

    Evidence ChIP, promoter reporter assays, knockdown/overexpression, xenograft and 3T3-L1 models (2013–2017)

    PMID:23754749 PMID:28134935 PMID:28889000

    Open questions at the time
    • Whether these factors act combinatorially is untested
    • Quantitative contribution of transcription vs PTM to ATG4B activity unknown
  9. 2020 Medium

    Quantitative biochemistry defined the bipartite recognition logic—a low-nanomolar ubiquitin-like core interaction plus a ≥1000-fold C-terminal-tail contribution and a molecular-ruler readout of the LC3 cleavage motif—explaining ATG4B fidelity distinct from pathogen mimics.

    Evidence Semisynthetic LC3-PE substrates, ATG4B truncation mutants, KD/IC50 measurements, molecular docking

    PMID:32686895 PMID:36264309

    Open questions at the time
    • Structural model of the C-terminal tail engagement not crystallographically resolved
    • How modifications alter these binding parameters not measured
  10. 2023 Medium

    Newer post-translational and contextual regulators expanded the network: UBE3C K33-ubiquitination, EP300/SIRT2 acetylation switching, copper-induced oxidative inhibition, and roles in melanosome trafficking, centrosomal LC3 processing for cell cycle, and selective TBK1 degradation broadened ATG4B function beyond bulk autophagy.

    Evidence MS interactome and chain typing, deacetylation/acetylation assays with sirt2−/− mice, in vitro copper inhibition, live imaging, CRISPR knockout, IFN reporter assays (2017–2024)

    PMID:28598240 PMID:35349929 PMID:36056541 PMID:37434364 PMID:37701987 PMID:38146933

    Open questions at the time
    • TBK1-degradation finding rests on knockdown/co-IP only
    • Mechanistic link between centrosomal LC3 processing and cell-cycle machinery undefined
    • Whether copper oligomerization is physiologically relevant beyond Wilson disease unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing post-translational modifications are temporally ordered and spatially partitioned to set ATG4B activity at distinct membranes (phagophore vs melanosome vs centrosome) remains unresolved.
  • No integrated model of PTM hierarchy and crosstalk
  • No structural account of how modifications remodel substrate binding
  • Spatial control of ATG4B targeting to non-canonical membranes uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 4 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0031410 cytoplasmic vesicle 2 GO:0005739 mitochondrion 1 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 4 R-HSA-1640170 Cell Cycle 1 R-HSA-168256 Immune System 1
Partners
GABARAPLC3BMST4RAB7BRNF5TMED10UBE3CULK1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Crystal structures of catalytically inert human ATG4B in complex with processed and unprocessed LC3 reveal the mechanism of substrate recognition and catalysis: the regulatory loop masking the active site entrance is lifted by LC3 Phe119, forming a groove for the LC3 tail to enter the active site, while the N-terminal tail masking the active site exit is detached, exposing a flat surface that may enable access to membrane-bound LC3-PE. X-ray crystallography of ATG4B–LC3 complex (catalytically inert mutant); structural analysis of conformational changes upon substrate binding The EMBO journal High 19322194
2005 Crystal structure of human ATG4B at 2.0 Å resolution shows it is a cysteine protease with a catalytic triad of Cys74, His280, and Asp278, comprising a 'protease domain' resembling papain superfamily cysteine proteinases and an 'auxiliary domain' of unknown function; residues R229 and W142 are specifically essential for substrate recognition and catalysis of both precursor processing and de-conjugation. X-ray crystallography; site-directed mutagenesis of active-site residues Journal of molecular biology High 16325851
2003 A single protease, ATG4B (Apg4B/autophagin-1), is the processing and deconjugating enzyme for all four mammalian ATG8 homologues: GATE-16, GABARAP, MAP1-LC3, and Apg8L, as demonstrated by electrophilic activity-based probes that form specific adducts in crude cell lysates. Activity-based protein profiling with electrophilic ubiquitin-like probes; adduct formation in cell lysates The Journal of biological chemistry High 14530254
2017 MST4 (STK26) kinase phosphorylates ATG4B at serine residue 383, which stimulates ATG4B protease activity and increases autophagic flux; radiation induces MST4 expression, ATG4B phosphorylation, and autophagy; inhibition of MST4 or ATG4B suppresses autophagy and glioblastoma tumorigenicity. In vitro kinase assay; phospho-specific antibodies; genetic knockdown/overexpression; xenograft mouse models Cancer cell High 29232556
2017 ULK1 phosphorylates ATG4B at serine 316, resulting in inhibition of its catalytic activity both in vitro and in vivo; the phosphatase PP2A-PP2R3B removes this inhibitory phosphorylation, providing a reversible phospho-switch that regulates ATG4B activity to coordinate LC3 processing during autophagy. In vitro kinase assay; phospho-mimetic and phospho-deficient mutants; co-immunoprecipitation; cell-based autophagy assays Nature communications High 28821708
2015 Phosphorylation of ATG4B at Ser-383 and Ser-392 increases its hydrolase activity toward LC3 substrate; phosphorylation-deficient ATG4B shows reduced interactions with lipid-conjugated LC3 (but not unconjugated LC3), and reconstitution of atg4b−/− cells with phospho-deficient ATG4B demonstrates a role for these sites in LC3 delipidation and autophagic flux. In vitro biochemical hydrolase assay; reconstitution of atg4b−/− cells; co-immunoprecipitation; flow cytometry The Journal of biological chemistry High 26378241
2015 A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity through reactive oxygen species: stress conditions induce ROS via REDD1/TXNIP, which suppresses the redox-sensitive ATG4B cysteine endopeptidase activity, thereby reducing LC3B delipidation and activating autophagy; loss of REDD1 or TXNIP increases ATG4B catalytic activity and causes failed autophagy in vivo. ATG4B catalytic activity assays; REDD1−/− and TXNIP knockout cells/mice; ROS measurement; mitochondrial function assays Nature communications High 25916556
2012 The membrane-associated E3 ubiquitin ligase RNF5 ubiquitinates ATG4B and controls its stability, specifically regulating the membranal fraction of ATG4B and thereby limiting LC3 processing, phagophore formation, and basal autophagy levels; RNF5 mutants retaining E3 ligase activity but unable to associate with ATG4B no longer affect LC3 puncta. Co-immunoprecipitation; ubiquitination assays; RNF5−/− MEFs; LC3 puncta quantification; bacterial infection models PLoS genetics High 23093945
2017 ATG4B S-nitrosation at Cys189 and Cys292 (induced by high glucose/NO) compromises both its pro-LC3 processing and LC3-PE deconjugation activities, suppressing autophagosome biogenesis and causing neurotoxicity; GABARAPL1 processing is least affected by this modification compared to other substrates. LC-MS/MS-based quantitative S-nitrosation proteomics; site-directed mutagenesis (Cys189, Cys292); ATG4B activity assays; mRFP-GFP-LC3 flux analysis; neuronal cell culture models Autophagy High 28633005
2018 AKT phosphorylates ATG4B at Ser34, which has little effect on autophagic flux but promotes the Warburg effect (increased lactate, glucose consumption, decreased oxygen consumption) in HCC cells by impairing mitochondrial function including F1Fo-ATP synthase activity; Ser34 phosphorylation enhances ATG4B mitochondrial localization and co-localization with F1Fo-ATP synthase. In vitro kinase assay; phospho-site mutagenesis; metabolic assays; subcellular fractionation; co-immunoprecipitation; submitochondrial particle reconstitution assay Autophagy Medium 29165041
2021 PFKP (phosphofructokinase 1 platelet isoform) acts as a protein kinase that phosphorylates ATG4B at Ser34 under amino acid deprivation; this phosphorylation enhances ATG4B protease activity and autophagic flux; amino acid deprivation strengthens the ATG4B–PFKP interaction, and PFKP loss reduces LC3-II degradation. Tandem affinity purification/mass spectrometry; co-immunoprecipitation; in vitro kinase assay; CRISPR/Cas9 knockout; phospho-site mutagenesis; autophagy flux assays Cellular signalling Medium 33607258
2024 UBE3C is an E3 ubiquitin ligase of ATG4B that assembles K33-branched ubiquitin chains on ATG4B at Lys119 without causing ATG4B degradation; K33-ubiquitination reduces ATG4B protease activity and ATG4B–LC3 interaction, inhibiting autophagic flux; under starvation, the ATG4B–UBE3C interaction decreases and K33-linked ubiquitin chains are removed. Mass spectrometry identification of interactors; co-immunoprecipitation; ubiquitin chain-type analysis; ATG4B activity assays; site-directed mutagenesis (K119R); overexpression/knockout experiments Autophagy Medium 38146933
2022 SIRT2 deacetylates ATG4B at lysine 39 (K39), enhancing ATG4B protease activity and autophagic flux; EP300/p300 acetylates ATG4B K39, antagonizing SIRT2; starvation reduces the CCNE-CDK2 complex, decreases SIRT2 Ser331 phosphorylation, activates SIRT2, promotes ATG4B K39 deacetylation, and initiates autophagy; validated in sirt2−/− mice. Co-immunoprecipitation; ATG4B activity assays; site-directed mutagenesis (K39); sirt2−/− mouse model; phosphorylation/deacetylation biochemical assays Autophagy Medium 36056541
2019 TMED10 directly binds to ATG4B and negatively regulates its proteolytic activity for LC3 cleavage; this interaction is diminished under autophagy-activating conditions (rapamycin, serum deprivation); in Alzheimer disease, reduced TMED10 expression increases ATG4B activity and autophagy. Bimolecular fluorescence complementation (BiFC); co-immunoprecipitation; ATG4B protease activity assays; siRNA knockdown; amyloid-β treatment experiments Autophagy Medium 30821607
2017 The small GTPase Rab7b interacts and co-localizes with ATG4B on vesicles; Rab7b depletion increases autophagic flux, and Rab7b regulates LC3 processing by modulating ATG4B activity, identifying Rab7b as a negative regulator of autophagy through its interaction with ATG4B. Co-immunoprecipitation; co-localization by fluorescence microscopy; autophagic flux assays; Rab7b knockdown EMBO reports Medium 28835545
2006 Human ATG4B (but not ATG4A or ATG4C) cleaves the C-terminus of Atg8L in vitro, and Atg8L undergoes E1 (ATG7) and E2 (ATG3) conjugation reactions, identifying it as the fourth mammalian ATG8-conjugation modifier processed by ATG4B. In vitro cleavage assay; E1/E2 intermediate trapping with catalytic mutants; subcellular fractionation; fluorescence co-localization The FEBS journal Medium 16704426
2006 ATG4B knockdown in PC12 cells suppresses the in vitro cleavage of recombinant proLC3 to LC3-I, confirming ATG4B plays a major role in LC3 processing; ATG4B protein and mRNA are ubiquitously expressed across rat tissues with highest levels in brain (particularly neurons of cerebellum and olfactory bulb) and testis. RNA interference; recombinant proLC3 cleavage assay; Western blot; immunohistochemistry; in situ hybridization Autophagy Medium 16874114
2009 Overexpression of catalytically inactive ATG4B(C74A) mutant sequesters LC3 paralogues, blocks formation of the ATG7–LC3 intermediate, causes accumulation of ATG5-positive autophagic structures, and prevents autophagosome closure, demonstrating that excess ATG4B mutant inhibits autophagy at the level of LC3 lipidation and autophagosome sealing. Overexpression of dominant-negative mutant; immunofluorescence of autophagic structures; biochemical intermediate trapping assays Autophagy Medium 19104152
2013 C/EBPβ transcriptionally activates Atg4b expression by directly binding to its promoter, which is required for autophagy induction during adipocyte differentiation; Atg4b-dependent autophagy mediates degradation of Klf2 and Klf3 (negative regulators of adipogenesis) via the adaptor protein p62/SQSTM1. ChIP assay; promoter reporter assays; ATG4B knockdown/overexpression in 3T3-L1 cells; mouse models; p62 interaction studies Molecular and cellular biology Medium 23754749
2017 Egr-1 transcription factor binds to the ATG4B promoter upon ionizing radiation and upregulates ATG4B expression in HCC cells, thereby inducing protective autophagy and radioresistance; dominant-negative Egr-1 suppresses radiation-induced ATG4B expression, autophagy, and cell migration. Luciferase reporter assay; chromatin immunoprecipitation (ChIP); dominant-negative Egr-1 overexpression; autophagy and clonogenic survival assays Oncogenesis Medium 28134935
2017 ATG4B and LC3B mediate melanosome trafficking on cytoskeletal tracks: LC3B labels melanosomes and enables assembly of a microtubule translocon complex for intracellular positioning; ATG4B enzymatically delipidates LC3B from melanosomal membranes at the microtubule-actin crossover junction; melanosomes transferred to keratinocytes lack melanocyte-specific LC3B. Live-cell fluorescence imaging; enzymatic ATG4B activity assays; cytoskeletal co-localization; keratinocyte transfer assays Autophagy Medium 28598240
2022 ATG4B localizes to early autophagic membranes in an LC3B-dependent manner; during autophagy, ATG4B and LC3B undergo rapid cytosol/isolation membrane exchange but not at completed autophagosomes; ATG4B activity controls the efficiency of autophagosome formation by impacting LC3B membrane binding/dissociation. Fluorescence recovery after photobleaching (FRAP) of GFP-tagged ATG4B and LC3B in living cells; autophagy inhibitor experiments Journal of molecular cell biology Medium 34562084
2013 ATG4B interacts with Bcl-2 by co-immunoprecipitation, and ATG4B upregulation promotes disassociation of the Bcl-2–Beclin1 complex, releasing Beclin1 to activate the autophagic pathway in cadmium-treated A549 cells. Co-immunoprecipitation; ATG4B knockdown/overexpression; Bcl-2–Beclin1 interaction assays; autophagy flux measurements Free radical biology & medicine Low 30458278
2015 SLC27A4 directly interacts with ATG4B (by co-IP and GST pull-down) in lung cancer cells, maintains ATG4B protein stability and intracellular concentration, and thereby facilitates autophagy induction in response to nutrient deprivation or chemotherapy stress. Tandem affinity purification/mass spectrometry; co-immunoprecipitation; GST pull-down assay; siRNA knockdown; autophagic flux assays Tumour biology Low 26662804
2022 Copper ion (but not other metal ions) directly inhibits ATG4B protease activity and induces ATG4B cysteine oxidation-dependent oligomer formation; copper promotes formation of insoluble ATG4B aggregates along with p62- and ubiquitin-positive aggregates; ATG4B overexpression partially reduces Mallory body formation and rescues impaired autophagy in Wilson disease cell models. In vitro ATG4B activity assay with copper; cysteine oxidation/oligomerization assays; cell-based autophagy flux assays; Wilson disease cell model Redox biology Medium 35349929
2020 ATG4B cleaves LC3-PE using a molecular ruler mechanism dependent on the LC3 C-terminal motif (residues Gln116, Phe119, Gly120); the C-terminal tail of ATG4B is required for LC3 binding and proteolysis (contributing ≥1000-fold to binding affinity) but not for cleavage of a short peptide substrate; distinct from the Legionella effector RavZ which lacks this molecular ruler mechanism. Semisynthetic LC3-PE proteins with C-terminal mutations; molecular docking; biochemical cleavage assays; ATG4B truncation mutants Chembiochem Medium 32686895
2022 Biochemical and biophysical characterization shows the ubiquitin-like core of LC3B (residues 1–115, lacking the C-terminal cleavage site) binds full-length ATG4B with a KD in the low nanomolar range (10–30-fold tighter than pro-LC3B substrate); the C-terminal tail of ATG4B contributes ≥1000-fold higher binding affinity; binding of LC3B-115 does not alter the ATG4B active-site conformation, supporting a bipartite binding model. Biochemical binding assays (KD measurement); inhibition assays (IC50); ATG4B truncation mutants; peptide substrate cleavage assays Biochemistry Medium 36264309
2023 ATG4B promotes GABARAP-directed selective autophagic degradation of TBK1, thereby antagonizing antiviral type-I interferon signaling; ATG4B knockdown enhances IFN signaling and antiviral immunity. siRNA knockdown; co-immunoprecipitation; autophagic flux assays; IFN reporter assays; viral replication assays Autophagy Low 37434364
2019 ATG4B host cysteine protease can hydrolyze the substrate of EV71 3C protease with comparable activity, and genetic disruption of ATG4B reduces EV71 viral proliferation in vivo, identifying ATG4B as indispensable for EV71 replication. Activity-based protein profiling (ABP); in vitro substrate cleavage assays; ATG4B genetic disruption; viral titer assays Journal of virology Medium 31554687
2021 SIRT3 deacetylates ATG4B, and DHM (dihydromyricetin) increases SIRT3 expression leading to SIRT3-mediated ATG4B deacetylation, upregulating ATG4B protein levels and inducing autophagy to attenuate palmitic acid-induced oxidative stress in hepatocytes; the protective effect is abolished in SIRT3-inhibited or ATG4B heterozygous knockout cells. Western blot for ATG4B acetylation; SIRT3 inhibitor treatment; ATG4B+/− heterozygous knockout cells; ROS and mitochondrial function assays Nutrition & metabolism Low 34503544
2023 ATG4B accumulates in pancreatic acinar cells after ethanol treatment, directly inhibits autophagosome formation by reducing LC3-II levels through enhanced ATG4B enzymatic activity and strengthened interaction with LC3-II; adenoviral ATG4B overexpression inhibits autophagy and aggravates trypsinogen activation and necrosis; shRNA ATG4B knockdown enhances autophagosome formation and alleviates ethanol-induced acinar cell damage. Mouse model of alcoholic pancreatitis; adenoviral overexpression; shRNA knockdown; ATG4B activity assays; LC3-II quantification; trypsinogen activation assays American journal of physiology. Gastrointestinal and liver physiology Medium 37431575
2017 HSF1 transcription factor upregulates ATG4B expression by directly binding to the ATG4B gene promoter at position −1429 to −1417, thereby enhancing epirubicin-induced protective autophagy and reducing HCC cell sensitivity to chemotherapy. Luciferase reporter assay; chromatin immunoprecipitation (ChIP); HSF1/ATG4B knockdown; xenograft mouse models Cancer letters Medium 28889000
2023 Pro-LC3B accumulated aberrantly at the centrosome upon ATG4B knockout, with concomitant increases in centrosomal proteins PCM1 and CEP131; this was rescued by exogenous ATG4B, revealing a role for ATG4B in processing LC3B at the centrosome to permit normal cell cycle progression; ATG4B and ATG4A double knockout causes delays in both G1-S phase transition and mitosis. CRISPR/Cas9 ATG4B/ATG4A single and double knockout; immunofluorescence; rescue experiments; cell cycle analysis Journal of cell science Medium 37701987

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. The EMBO journal 312 19322194
2003 A single protease, Apg4B, is specific for the autophagy-related ubiquitin-like proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L. The Journal of biological chemistry 208 14530254
2014 A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 206 25483883
2017 MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. Cancer cell 202 29232556
2014 The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells. Blood 172 24755409
2015 A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity. Nature communications 169 25916556
2015 Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis. Autophagy 136 25906080
2018 Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo. Autophagy 121 30176161
2017 A reversible phospho-switch mediated by ULK1 regulates the activity of autophagy protease ATG4B. Nature communications 118 28821708
2013 7-Ketocholesterol induces autophagy in vascular smooth muscle cells through Nox4 and Atg4B. The American journal of pathology 106 23770348
2012 Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection. PLoS genetics 100 23093945
2019 lncRNA KCNQ1OT1 enhances the chemoresistance of oxaliplatin in colon cancer by targeting the miR-34a/ATG4B pathway. OncoTargets and therapy 99 31040703
2013 Transactivation of Atg4b by C/EBPβ promotes autophagy to facilitate adipogenesis. Molecular and cellular biology 86 23754749
2017 Autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia. Autophagy 85 28633005
2013 ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis. Autophagy 83 23782979
2018 Targeting the miR-665-3p-ATG4B-autophagy axis relieves inflammation and apoptosis in intestinal ischemia/reperfusion. Cell death & disease 80 29706629
2015 ATG4B (Autophagin-1) phosphorylation modulates autophagy. The Journal of biological chemistry 80 26378241
2005 The crystal structure of human Atg4b, a processing and de-conjugating enzyme for autophagosome-forming modifiers. Journal of molecular biology 76 16325851
2014 ATG4B promotes colorectal cancer growth independent of autophagic flux. Autophagy 73 24991826
2016 Identification of breast cancer cell subtypes sensitive to ATG4B inhibition. Oncotarget 61 27556700
2017 ATG4B inhibitors with a benzotropolone core structure block autophagy and augment efficiency of chemotherapy in mice. Biochemical pharmacology 60 28642033
2016 Discovery of Fluoromethylketone-Based Peptidomimetics as Covalent ATG4B (Autophagin-1) Inhibitors. ACS medicinal chemistry letters 58 27563406
2015 Methylation-induced silencing of miR-34a enhances chemoresistance by directly upregulating ATG4B-induced autophagy through AMPK/mTOR pathway in prostate cancer. Oncology reports 57 26499184
2017 Egr-1 regulates irradiation-induced autophagy through Atg4B to promote radioresistance in hepatocellular carcinoma cells. Oncogenesis 55 28134935
2023 Circ-0000953 deficiency exacerbates podocyte injury and autophagy disorder by targeting Mir665-3p-Atg4b in diabetic nephropathy. Autophagy 53 38050963
2022 Membrane dynamics of ATG4B and LC3 in autophagosome formation. Journal of molecular cell biology 50 34562084
2017 Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal tracks. Autophagy 50 28598240
2015 Systems biology-based discovery of a potential Atg4B agonist (Flubendazole) that induces autophagy in breast cancer. Molecular bioSystems 50 26299935
2018 The interaction of Atg4B and Bcl-2 plays an important role in Cd-induced crosstalk between apoptosis and autophagy through disassociation of Bcl-2-Beclin1 in A549 cells. Free radical biology & medicine 49 30458278
2018 AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells. Autophagy 46 29165041
2006 Atg8L/Apg8L is the fourth mammalian modifier of mammalian Atg8 conjugation mediated by human Atg4B, Atg7 and Atg3. The FEBS journal 46 16704426
2019 SNHG16 promotes osteosarcoma progression and enhances cisplatin resistance by sponging miR-16 to upregulate ATG4B expression. Biochemical and biophysical research communications 45 31427084
2016 Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin. Autophagy 44 27097054
2018 A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B. Scientific reports 43 30076329
2006 Effects of RNA interference of Atg4B on the limited proteolysis of LC3 in PC12 cells and expression of Atg4B in various rat tissues. Autophagy 43 16874114
2018 ATG4B inhibitor FMK-9a induces autophagy independent on its enzyme inhibition. Archives of biochemistry and biophysics 41 29510087
2022 Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer. Cell death & disease 39 35184132
2019 Down-regulated TMED10 in Alzheimer disease induces autophagy via ATG4B activation. Autophagy 38 30821607
2017 HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells. Cancer letters 38 28889000
2021 MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B. Acta pharmaceutica Sinica. B 35 35646533
2019 On ATG4B as Drug Target for Treatment of Solid Tumours-The Knowns and the Unknowns. Cells 35 31878323
2010 Histopathological and neurological features of Atg4b knockout mice. Veterinary pathology 35 20634410
2022 Post-Translational Modifications of ATG4B in the Regulation of Autophagy. Cells 34 35456009
2021 LncRNA CRNDE Promotes ATG4B-Mediated Autophagy and Alleviates the Sensitivity of Sorafenib in Hepatocellular Carcinoma Cells. Frontiers in cell and developmental biology 34 34409031
2017 Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 29169176
2015 Development of fluorescent peptide substrates and assays for the key autophagy-initiating cysteine protease enzyme, ATG4B. Bioorganic & medicinal chemistry 33 25979376
2015 SLC27A4 regulate ATG4B activity and control reactions to chemotherapeutics-induced autophagy in human lung cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 33 26662804
2013 Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy. Biochemical and biophysical research communications 33 24184480
2017 Interleukin-6 downregulated vascular smooth muscle cell contractile proteins via ATG4B-mediated autophagy in thoracic aortic dissection. Heart and vessels 32 28965202
2022 The Effect of Allograft Inflammatory Factor-1 on Inflammation, Oxidative Stress, and Autophagy via miR-34a/ATG4B Pathway in Diabetic Kidney Disease. Oxidative medicine and cellular longevity 31 36345369
2017 Rab7b modulates autophagic flux by interacting with Atg4B. EMBO reports 31 28835545
2014 Development of fluorescent substrates and assays for the key autophagy-related cysteine protease enzyme, ATG4B. Assay and drug development technologies 31 24735444
2017 Let-7i-Induced Atg4B Suppression Is Essential for Autophagy of Placental Trophoblast in Preeclampsia. Journal of cellular physiology 29 27770612
2009 Atg4B(C74A) hampers autophagosome closure: a useful protein for inhibiting autophagy. Autophagy 29 19104152
2016 Identification of New ATG4B Inhibitors Based on a Novel High-Throughput Screening Platform. SLAS discovery : advancing life sciences R & D 27 26993319
2020 Targeting Atg4B for cancer therapy: Chemical mediators. European journal of medicinal chemistry 25 33077263
2021 miR-27a-5p-Abundant Small Extracellular Vesicles Derived From Epimedium-Preconditioned Bone Mesenchymal Stem Cells Stimulate Osteogenesis by Targeting Atg4B-Mediated Autophagy. Frontiers in cell and developmental biology 24 34621733
2021 Dihydromyricetin attenuates palmitic acid-induced oxidative stress by promoting autophagy via SIRT3-ATG4B signaling in hepatocytes. Nutrition & metabolism 23 34503544
2019 MiR-129-3p favors intracellular BCG survival in RAW264.7 cells by inhibiting autophagy via Atg4b. Cellular immunology 22 30782398
2019 Xanthium strumarium Fruit Extract Inhibits ATG4B and Diminishes the Proliferation and Metastatic Characteristics of Colorectal Cancer Cells. Toxins 22 31159487
2017 The downregulation of ATG4B mediated by microRNA-34a/34c-5p suppresses rapamycin-induced autophagy. Iranian journal of basic medical sciences 22 29147488
2022 Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation. Redox biology 21 35349929
2022 Discovery and mechanism studies of a novel ATG4B inhibitor Ebselen by drug repurposing and its anti-colorectal cancer effects in mice. Cell & bioscience 21 36539845
2020 New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function. Cancers 20 32532053
2020 Distinct Mechanisms for Processing Autophagy Protein LC3-PE by RavZ and ATG4B. Chembiochem : a European journal of chemical biology 20 32686895
2018 Identification of Kinases and Phosphatases That Regulate ATG4B Activity by siRNA and Small Molecule Screening in Cells. Frontiers in cell and developmental biology 19 30443548
2024 UBE3C tunes autophagy via ATG4B ubiquitination. Autophagy 18 38146933
2023 YY1 is regulated by ALKBH5-mediated m6A modification and promotes autophagy and cancer progression through targeting ATG4B. Aging 18 37724907
2012 Imaging protein complex formation in the autophagy pathway: analysis of the interaction of LC3 and Atg4B(C74A) in live cells using Förster resonance energy transfer and fluorescence recovery after photobleaching. Journal of biomedical optics 18 22352642
2019 ERBB2-modulated ATG4B and autophagic cell death in human ARPE19 during oxidative stress. PloS one 16 30870514
2023 An ATG4B inhibitor blocks autophagy and sensitizes Sorafenib inhibition activities in HCC tumor cells. Bioorganic & medicinal chemistry 15 37018878
2018 Investigating miRNA-661 and ATG4-B mRNA expression as potential biomarkers for hepatocellular carcinoma. Biomarkers in medicine 15 29441798
2023 ATG4B antagonizes antiviral immunity by GABARAP-directed autophagic degradation of TBK1. Autophagy 14 37434364
2020 Targeting the MicroRNA-490-3p-ATG4B-Autophagy Axis Relieves Myocardial Injury in Ischemia Reperfusion. Journal of cardiovascular translational research 14 32474761
2018 Impaired autophagic activity and ATG4B deficiency are associated with increased endoplasmic reticulum stress-induced lung injury. Aging 14 30147026
2021 ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma. Frontiers in oncology 13 34868951
2019 Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay. European journal of medicinal chemistry 13 31226656
2019 Activity-Based Protein Profiling Identifies ATG4B as a Key Host Factor for Enterovirus 71 Proliferation. Journal of virology 13 31554687
2016 Inhibitor screening and enzymatic activity determination for autophagy target Atg4B using a gel electrophoresis-based assay. European journal of medicinal chemistry 13 27517808
2020 MiR-449a attenuates autophagy of T-cell lymphoma cells by downregulating ATG4B expression. BMB reports 11 32172731
2017 EWS-FLI1 positively regulates autophagy by increasing ATG4B expression in Ewing sarcoma cells. International journal of molecular medicine 11 28902354
2023 m6A reader HNRNPA2B1 destabilization of ATG4B regulates autophagic activity, proliferation and olaparib sensitivity in breast cancer. Experimental cell research 10 36693492
2023 Ethanol inhibits pancreatic acinar cell autophagy through upregulation of ATG4B, mediating pathological responses of alcoholic pancreatitis. American journal of physiology. Gastrointestinal and liver physiology 10 37431575
2021 PFKP facilitates ATG4B phosphorylation during amino acid deprivation-induced autophagy. Cellular signalling 10 33607258
2021 Rno_circRNA_016194 might be involved in the testicular injury induced by long-term formaldehyde exposure via rno-miR-449a-5p mediated Atg4b activation. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 10 34265366
2019 Synthesis and evaluation of novel benzotropolones as Atg4B inhibiting autophagy blockers. Bioorganic chemistry 10 30884310
2023 The LC3B FRET biosensor monitors the modes of action of ATG4B during autophagy in living cells. Autophagy 9 36814061
2022 Involvement of acetylation of ATG4B in controlling autophagy induction. Autophagy 9 36056541
2020 The cysteine protease ATG4B of Trichinella spiralis promotes larval invasion into the intestine of the host. Veterinary research 9 32448368
2023 ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer. Cancer cell international 8 37038218
2024 Docosahexaenoic acid enhances the treatment efficacy for castration-resistant prostate cancer by inhibiting autophagy through Atg4B inhibition. Archives of biochemistry and biophysics 7 39181384
2023 FAT1 inhibits AML autophagy and proliferation via downregulating ATG4B expression. Biochimica et biophysica acta. General subjects 7 37952564
2022 LC3B Binds to the Autophagy Protease ATG4b with High Affinity Using a Bipartite Interface. Biochemistry 6 36264309
2018 Autophagy related markers (Beclin-1 and ATG4B) are strongly expressed in Wilms' tumor and correlate with favorable histology. Histology and histopathology 6 29989143
2015 The Xenopus laevis Atg4B Protease: Insights into Substrate Recognition and Application for Tag Removal from Proteins Expressed in Pro- and Eukaryotic Hosts. PloS one 6 25923686
2023 Loss of ATG4B and ATG4A results in two-stage cell cycle defects in pancreatic ductal adenocarcinoma cells. Journal of cell science 5 37701987
2024 CircRNA regulates the liquid-liquid phase separation of ATG4B, a novel strategy to inhibit cancer metastasis? Cell stress 4 38803355
2024 Targeting STK26 and ATG4B: miR-22-3p as a modulator of autophagy and tumor progression in HCC. Translational oncology 4 39608212
2023 Atg4b Overexpression Extends Lifespan and Healthspan in Drosophila melanogaster. International journal of molecular sciences 4 37373039
2022 ATG4B hinders porcine epidemic diarrhea virus replication through interacting with TRAF3 and activating type-I IFN signaling. Veterinary microbiology 4 36049346

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